通过利用肿瘤微环境（TME）来达到细胞内氧化还原不平衡已成为癌症治疗的一种有前景的策略。在本研究中，我们通过修饰一种金属有机骨架Fe/ZIF-8与透明质酸（HA）靶向，开发了一种多功能纳米佐剂，称为GITFe/Z-HA。纳米载体被装载了葡萄糖氧化酶（Gox）、新吲哚菁绿（IR820）和噻扎咪（TPZ）。此设计旨在实现肿瘤细胞内的一个级联反应，由Gox、Fe3+和IR820介导，消耗固有的葡萄糖和氧气，从而导致产生反应性氧化物（ROS）的增加。这个级联反应创造了一个缺氧的环境，有利于TPZ发挥其治疗作用。因此，光热治疗（PTT）、光动力治疗（PDT）和化学治疗的组合展示了良好的协同效应。此外，由这种治疗方法引起的ROS/谷胱甘肽（GSH）不平衡，以及PTT促进免疫原性细胞死亡（ICD），促使损伤相关分子模式的释放和CD8+淋巴细胞浸润，使免疫检查点阻断（αPD-L1）反应敏感化，从而引发系统性的抗肿瘤免疫应答。综上所述，这种由环境刺激的多途径驱动的综合治疗方案克服了单一治疗方式的局限性，从而改善了肿瘤预后。此外，这些发现为调节肿瘤免疫微环境的策略提供了有价值的见解。版权所有 © 2023. Elsevier B.V.出版。

Intracellular redox imbalance, achieved by exploiting the tumor microenvironment (TME), has emerged as a promising strategy for cancer therapy. In this study, we developed a multifunctional nanoadjuvant, termed GITFe/Z-HA, by modified a metal-organic backbone Fe/ZIF-8 with hyaluronic acid (HA) targeting. The nanocarriers were loaded with glucose oxidase (Gox), neoindocyanine green (IR820) and tilazamine (TPZ). This design aimed to achieve a cascade reaction within tumor cells, mediated by Gox, Fe3+, and IR820, which consumes intrinsic glucose and oxygen, leading to an elevated production of reactive oxygen species (ROS). This cascade reaction creates a hypoxic environment conducive for TPZ to exert its therapeutic action. Consequently, the combination of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy demonstrates a good synergistic effect. Moreover, the imbalanced ROS/glutathione (GSH) induced by this treatment approach, along with PTT, promote immunogenic cell death (ICD). This ICD triggers the release of damage-related molecular patterns and CD8+ lymphocyte infiltration sensitizes the immune checkpoint blockade (αPD-L1) response, thereby eliciting a systemic anti-tumor immune response. Collectively, this comprehensive treatment regimen, driven by environmentally stimulated multiple pathways, overcomes the limitations of single therapeutic modalities, thereby improving tumor outcomes. Additionally, these findings provide valuable insights for strategies aimed at modulating the tumor immune microenvironment.Copyright © 2023. Published by Elsevier B.V.